1,2 - methylene - 6,7 - difluoromethylene and 1,2,6,7 - bis(difluoromethylene) pregnanes and processes for their preparation

ABSTRACT

THIS DISCLOSES 3-KETO-$**4-PREGENE AND O-KETO-$**4-19NORPREGNENE STEROID COMPOUNDS WHICH CONTAIN 6,7-METHYLENE, 6,7 MONOHALOMETHYLENE OR 6,7-DIHALOMETHYLENE GROUPING. IT ALSO DISCLOSES 3-KETO-$**4-PREGNENE STEROID COMPOUNDS WHICH CONTAIN 1,2=METHYLENE-6,7-DIFLUE STEROID METHYLENE AND 1,2,6,7-BIS(DIFLUOROMETHYLENE) GROUPINGS. THESE COMPOUNDS CAN BE OPTIONALLY SUBSTITUTED AT ONE OR MORE OF THE C-6, C-9, C-11, C-16,C-17, C-16,17, C-21 AND/OR C-17,21 POSITIONS, ALSO TAUGHT ARE PROCESSES USEFUL FOR THE PREPARATION OF THESE COMPOUNDS. THESE COMPOUNDS ARE USEFUL IN ACCORDANCE WITH EXHIBITED CORTICOID, ANTI-INFLAMMATORY AND PROGESTATIONAL ACTIVITIES.

United States Patent U.S. Cl. 260-397.4 31 Claims ABSTRACT OF THEDISCLOSURE This discloses 3-keto-A -pregnene and 3-keto-A -19-norpregnene steroid compounds which contain 6,7-methylene,6,7-monohalomethylene or 6,7-dihalomethylene groupings. It alsodiscloses 3-keto-A -pregnene steroid compounds which contain1,2-methylene-6,7-difluoromethylene and 1,2;6,7-bis(difiuoromethylene)groupings. These compounds can be optionally substituted at one or moreof the C-6, C-9, C-ll, C16, C-17, C16,17, C-21 and/or C17,21 positions.Also taught are processes useful for the preparation of these compounds.These compounds are useful in accordance with exhibited corticoid,anti-inflammatory and progestational activities.

This is a continuation-in-part of Ser. No. 634,411, filed Apr. 11, 1967,now U.S. Pat No. 3,438,977, which is a continuation-in-part of Ser. No.499,092, filed Oct. 20, 1965, now abandoned, which is acontinuation-in-part of Ser. No. 486,226, filed Sept. 9, 1965, now U.S.Pat. No. 3,338,928. 2

This invention pertains to novel steroids, in particular to pregnanesand 19-norpregnanes having a cyclopropyl or halocyclopropyl ring fusedto the C-6,7 position of the molecule as represented by the followingskeletal steroid Formula A in which, for convenience and simplicity,only the novel grouping is depicted, each of X and Y be ing hydrogen,chloro or fluoro:

CXY

It also pertains to novel pregnanes having a difluorocyclopropyl groupfused to ecah of the C1,2 and C6,7 positions of the molecule and tonovel pregnanes having a 3,557,160 Patented Jan. 19, 1971 cyclopropylgroup fused to the C-1,2 position and a difluorocyclopropyl group fusedto the C6,7 position of the molecule. These compounds are respectivelyrepresented by skeletal Formulas B and C:

Specifically, this invention is directed at compounds which arediagrammatically represented by Formula I below:

CH3 (Firm R2 I it-A -33 ail 0 v 2 Z1 Y R wherein:

R is hydrogen, hydro$ry, fluoro, chloro, phosphato (including monoanddialkyl metal salts thereof), tetrahydropyran-2-yloxy,-tetrahydrofuran-Z-yloxy or a hydrocarbon carboxylic acyloxy group ofless than 12 carbon atoms;

R is hydrogen, hydroxy, a hydrocarbon carboxylic acyloXy group of lessthan 12 carbon atoms, or, when taken together with R one of groups v o nin which A is hydrogen or alkyl of up to eight carbon atoms and B ishydrogen or alkyl or aryl of up to eight carbon atoms; R is hydrogen,methylene, a-methyl, fl-methyl, u-chloro, a-fiuoro, a-hydroxy and(it-hydrocarbon carboxylic acyl oxy group of less than 12 carbon atoms,or, when taken together with R the group in which A is hydrogen or alkylof up to eight carbon atoms and B is hydrogen or alkyl or aryl of up toeight carbon atoms; a 1

R is hydrogen, chloro or fluoro;

R is hydrogen, hydroxy, keto or chloro, R and R being the same when R ishydrogen or chloro;

R is hydrogen, methyl, chloro or fluoro;

R is hydrogen or methyl;

Z is a carbon-carbon single bond or a carbon-carbon double bond, Z beinga single bond when R is hydrogen; and

Z is the group in which each of X and Y is hydrogen, chloro or fiuoro.

More particularly, the present invention is directed to1,2;6,7-bis(difluoromethylene)-3-keto-A -pregnenes which can berepresented by the Formulas H and HI:

CH3 CH2 on 3 on,

R3 MR i013: i

Rs: i REF-L1 i". F2 M 0 F3 1) (III) In addition, the present inventionis directed to 1,2- methylene-6,7-difiuoromethylene 3 keto A -pregneneswhich are represented by Formulas IV and V:

CH3 CH3 CHz-R CHg-R MR CH CH2 3 5 IR; A ti R CFz R F2 In Formulas II,III, IV and V and succeeding formulas,

R is hydrogen, fluoro or chloro;

R is hydrogen, hydroxy, or a hydrocarbon carboxylic acyloxy group ofless than 12 carbon atoms;

R is hydrogen, methylene, u-methyl, fl-methyl or, when taken togetherwith R the group in which A is hydrogen or alkyl of up to eight carbonatoms and B is hydrogen or alkyl or aryl of up to eight carbon atoms;

R is hydrogen, methyl, chloro or fluoro; and

R is the group in which R is hydrogen, tetrahydrofuran-Z-yl,tetrahydropyran-2yl or a hydrocarbon carboxylic acyl group of less than12 carbon atoms.

In each of the above formulas and in each of those which follow, thewavy lines (2) denote and include both 4 the alpha and betaconfigurations of the respective attached groupings.

The hydrocarbon carboxylic acyl and acyloxy groups of the presentinvention which are referred to in the definitions hereof contain lessthan 12 carbon atoms and can possess a straight, branched or cyclicchain structure which which is saturated, unsaturated or aromatic andoptionally substituted by functional groups, such as hydroxy, alkoxycontaining up to five carbon atoms, acyloxy containing up to 12 carbonatoms, nitIo, amino, halogeno, and the like. Typical conventional estersthus include acetate, propionate, enanthate, benzoate, trimethylacetate,t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate,fl-chloropropionate, adamantoate, bicyclo [2.2.2]octane-1-carboxylate,and the like.

Thus, the compounds of the present invention are of the pregnane steroidseries which include substituents characteristic of progestational andcorticoid steroids and a methylene, monohalomethylene or dihalomethylenegrouping fused to the C6,7 carbon atoms or a difluoromethylene groupfused to each pair of the C1,2 and C6,7 carbon atoms or a methylenegrouping fused to the Cl,2 carbon atoms and a difluoromethylene groupingfused to the C6,7 carbon atoms.

These compounds demonstrate hormonal properties characterized bycorticoid, anti-inflammatory and progestational activity. They areadministered in accordance with this activity via any of the normallyemployed routes including oral, parenteral and topical administrations.

For such administrations, the compounds can be suitably formed into apharmaceutically acceptable non-toxic composition via the incorporationof any of the usually employed excipients taking the form of powders,capsules, pellets, pills, solutions, creams, ointments, aerosols, and 35so forth. In addition, they can be administered in conjunction withother medicinal agents depending upon the specific condition beingtreated.

In administering these compounds, a convenient daily dosage regimenwhich can be adjusted according to the 40 degree of afliication isemployed. Most conditions respond well to treatment in the order ofmagnitude usually employed in the case of other compounds so used; thatis, via a daily dosage unit of from 0.001 mg. to mg. per kg. of bodyweight, the remainder being an inert vehicle or combination thereof.

In particular, the l,2;6,7-bis(difluoromethylene) com pounds of FormulasII and III and the 1,2-methylene-6,7- difluoromethylene compounds ofFormulas IV and V are progestational agents which are useful in thecontrol and regulation of fertility and in the management of variousmenstrual disorders. Such compounds are also anabolic agents and possessvarying degrees of anti-androgenic, anti-estrogenic andanti-gonadotrophic activities.

The synthesis of these compounds is accomplished in a number of Ways.For those compounds in which at least one of X and Y is chloro orfluoro, which include the 6,7-difiuoromethylene and1,2:6,7-bis(difluoromethylene) steroids, a 3-keto-A -pregnadiene,3-keto-19-nor- A -pregnadiene or a 3-keto-A -pregnatriene is treatedwith an alkali metal or alkaline earth metal salt of an acid of theformula W-CXY-COOH in which W is chloro, bromo or iodo, and X and Y areas above defined, with at least one of X or Y being chloro or fiuoro,such as bromochloroacetic acid, dichlroacetic acid, trichloroaceticacid, chlorofiuoroacetic acid, dichlorofluoroacetic acid,chlorodifluoroacetic acid, and the like. Preferably, the salt employedis an alkali metal salt, such as those of potassium, sodium and lithium.

The use of a dihaloacetate results in the formation of a fusedmonohalocyclopropyl grouping whereas the use of a trihaloacetate resultsin the formation of fused dihalo cyclopropyl groupings.

The reaction is performed at temperatures above tha at which the saltdecomposes, as evidenced by the evolution of carobn dioxide, thespecific temperature depending upon the particular polyhaloacetate andsteroid employed. Thus, in the case of sodium trichloroacetate, areaction temperature from 80 C. to 150 C. is generally used whereas withsodium chlorodifluoroacetate, a temperature from 150 C. to 180 C. isemployed. The reaction is preferably effected in the presence of aninert organic, non-aqueous solvent which is sufiiciently polar todissolve the polyhaloacetate. When the reaction is conducted in theconventional manner at atmospheric pressure, the solvent is selected sothat its boiling point is at or above the reaction temperature of thepolyhaloacetate, with the reaction being carried out at or below thereflux temperature. Alternatively, the reaction can be conducted undersuitable pressure to permit the use of lower boiling solvents.Particularly useful solvents are hydrocarbon polyethers such asdimethoxyethane, dimethyl diethylene glycol ether, dimethyl triethyleneglycol ether, and the like. Other solvents include dimethylformamide,dioxane, dimethylsulfoxide, and the like. The reaction time will alsovary depending upon the selection of solvent and reagents but may befollowed through observation of the ultraviolet absorption spectra, thereaction involving the loss of keto-conjugated unsaturation. Isolationof the product is accomplished via conventional procedures, such aschromatography.

By extending the described reaction conditions, upon completion ofaddition across the most remote (to the 3- keto group) conjugated doublebond, addition continues across the next most remote double bond. Thus,ultilization of a 43 starting com-pound provides initial addition acrossthe A double bond followed by similar addition across the A double bondforming the A derivative containing the C1,2;6,7 substitution. Theprocess of this invention can also be carried out on a compound alreadybearing a halocyclopropyl group. In these manners, the derivatives inthe pregnane series having the 1,2;6,7-bis(difluoromethylene) groupingsare readily pre pared.

In the case where each of X and Y is hydrogen, a 6,7- dichloromethyleneor 6,7-chloromethylene compound of the present invention, introduced asoutlined above, is reductively dehalogenated as with lithium aluminumhydride in organic solvent. Such a dehalogenation should be followed byan oxidation to regenerate any keto groups which then unprotected arereduced during the treatment with lithium aluminum hydride. Thus, forexample, a keto-6,7-dichloromethylene-A pregnene is first reductivelydehalogenated to a 3-hydroxy-6,7-methylenen -pregnene which upontreatment with 2,3-dichloro-5,6- dicyanobenzoquinone yields thecorresponding 3-keto-6,7- methyleneA -pregnene.

Alternatively, those compounds wherein each of X and Y is hydrogen, i.e.the 6,7-methylene derivatives, as well as the 1,2-methylene compoundsare prepared by treating a 3-keto-A -diene or 3-keto-A -diene withdimethylsulfoxonium methylide in dimethylsulfoxide. In the practice ofthis method, the starting steroid is contacted and maintained withdimethylsulfoxonium methylide (from about 0.9 mole to about 5.0 moles ofylide per mole of steroid), conveniently at about room temperature andfor a period of time sufiicient to complete the reaction. Thedimethylsulfoxonium methylide reactant is preferably prepared in situ byreacting trimethylsulfoxonium chloride or iodide in dimethylsulfoxidewith an alkali metal hydride, such as potassium or sodium hydride, underan inert atmosphere. Upon adding the staring diene steroid to thismixture containing dimethylsulfoxonium methylide reactant, the inertatmosphere is conveniently maintained for the duration of the reaction.

In the preparation of the 1,2-methylene-6,7-difluoro methylene compoundshereof via the above procedure, the 1,2-methylene group is preferablyintroduced into a 3-keto-A -diene starting steroid as described above. Adouble bond is then entered between the C-6.7 carbon atoms in the knownmanner to form the 1,2-methylene-3- keto-A -diene compounds. Thisderivative is then treated with the trihaloacetate salt as describedabove to form the desired product.

Alernatively, the same 1,Z-methylene-6,7-difiuoromethylene derivativescan be prepared substantially in the reverse order by first adding thedifluoromethylene group at C-6,7 of a 3-keto-A -diene steroid followedby the introduction therein of A unsaturation in the known method. This6,7 difluoromethylene 3-keto-A -diene derivative is then treated withthe dimethylsulfoxonium methylide to provide the desired product.

The addition of the methylene, monohalomethylene and dihalomethylenegroups in accordance with the procedures set forth herein at positionsC6,7 and Cl,2;6,7 is accomplished with the orientation of the resultantfused grouping including both isomeric alpha and beta configurations invariable ratios. The isomeric product mixture in each instance isconveniently and readily subjected to conventional techniques, such aschromatography, fractional crystallization, and the like, by which thealpha and beta isomers are separated by virtue of their differentphysical properties. Each isomer or isomeric mixture can thereafter besubjected to further elaboration as desired at other parts of themolecule as hereinafter set forth.

In some instances, one particular configurational isomer predominates inthe reaction mixture. Thus, for example, the presence of anllfl-hydroxyl orients the C6,7-methylene group predominantly to the betaconfiguration, but does not alter the usual alpha to beta ratio in thehalomethylene series. Beta addition in the halomethylene series isfavored by the presence of a 9a-halo substituent.

It will be understood that each of the isomers in each series isincluded within the scope of this invention.

In the practice of this reaction, it is also desirable to protecthydroxy groups through the utilization of derivatives which are easilyconvertible to hydroxy groups, such as esters and teterahydropyranylothers. This preference is not an absolute necessity, however, for whilefree hydroxy groups will often become involved in side reactions underthe conditions of the process, they can be readily regenerated byexecution of a mild alkaline hydrolysis after completion of theprincipal reaction. When each of R and R are hydroxy, for example,protection may be realized through formation of the16a,17a-isopropylidenedioxy derivative.

Starting compounds are chosen which already possess the necessaryunsaturation between the C6,7 carbon atoms or the C1,2 and C6,7 carbonatoms for the principal reactions hereof. Other desired elaboration atother parts of the molecule is also preferably present in the startingcompounds.

As previously described, the introduction of the 6,7- methylene,6,7-hal0methylene and 1,2;6,7 bis(difluoromethylene) groups is effectedupon compounds already bearing a A -diene or A -triene system. The M-diene unsaturation is introduced by treatment of a A -ene withchlorinal in the presence of ethyl acetate and acetic acid or xylene ort-butanol, the A -triene unsaturation by treatment of the A -diene withchloranil in the presence of (lower)alkanol, such as n-amyl alcohol.Alternatively, the A -diene system can be introduced at a stagesubsequent to the addition of the 6,7-methylene or -halomethylenegrouping, such as with 2,3 dichloro-S,6-dicyanobenzoquinone. Similarly,the A -diene system can be introduced at a stage subsequent to theaddition of the 1,2- methylene grouping, as described above. Theseprocedures are particularly convenient in preparing the1,2-methylene-6,7-difiuoromethylene compounds hereof.

ZI-fluoro, 21-chloro and 2l-unsubstituted derivatives are prepared fromthe corresponding 21-hydroxy compound, obtained upon hydrolysis of thel7oc,20;20,21-bi$- methylenedioxy intermediate with hydrofluoric acid orformic acid. Thus, the 21-hydroxy compound is treated withmethanesulfonyl chloride and the resulting ester is converted to thecorresponding 21-iodo intermediate by the action of sodium iodide. The2-iodo intermediate upon the action of silver fluoride or lithiumchloride yields the corresponding 21-fluoro or 21-ch1oro, respectively.Treatment of the 21-iodo intermediate instead with sodium metabisulfiteyields the 21-unsubstituted compound. The 21-iodo intermediate can alsobe obtained from 21- unsubstituted compounds through bromination andtreatment with sodium iodide.

With the exception of methylene, the substituents represented by R arepresent in the starting material as qualified above when R and R arehydroxy. The 16-methylene substituent is introduced after the principalreactions by formation of the 3,20-bis semicarbazone and treatment withacetic acid and pyruvic acid to yield the 3,20-diketo A -ene. Treatmentof this compound with diazomethane and pyrolysis produces thecorresponding 16- methyl-A -ene and epoxidation as with perbenzoic acidand ring opening with hydrogen bromide in acetic acid affords the16-methylene-17-ols.

Tertiary hydroxyl esterification procedures provide the 17a-estershereof. 16a,l7a-21Ctals and ketals are prepared through treatment of a16a,17a-dihydroxy compound with a ketone or aldehyde in the presence ofan acid, such as perchloric acid. The resulting acetal or ketal, forexample, a 16a,l7a-isopropylidenedioxy derivative may be utilized as afinal compound or as an intermediate, the group being cleaved withregeneration of the diol by the action of hydrofluoric acid.

The substituents represented by R are preferably present in the startingmaterial although the 6-fluoro and 6-chloro groups can be introducedupon treatment of the enol ether (prepared from the 3-keto-A -ene withethyl orthoformate) with N-chlorosuccinimide and perchloryl fluoride,respectively, followed again by double bond regeneration. Theregeneration of the double bond between C6,7 follows upon treatment ofthe 3-keto-substituted- A derivatives with chloranil to give thecorresponding A -diene directly or by first forming the enol ether ofthe 6-substituted componud and treating this with2,3-dichloro-5,6-dicyanobenzoquinone in the presence ofp-toluenesulfonic acid to alternatively give the corresponding A -dienecompound.

Following the principal reactions hereof, the C-3 position is elaboratedby first reducing the 3-keto group, such as with lithium aluminumhydride, sodium borohydride, and the like, in organic solution, such asisopropanol, followed by etherification of the resultant allylichydroxyl group with dihydropyran or dihydrofuran. This etherificationreaction is optionally conducted in the presence of an inert organicsolvent, such as benzene, diethyl ether, and the like, and in thepresence of small and catalytic amounts of any stable sulfonyl chloride,preferably p-toluenesulfonyl chloride, benzenesulfonyl chloride,methanesulfonyl chloride, p nitrobenzenesulfonyl chloride, and the like.

The 3fi-acylates hereof are prepared upon treatment of the 3,8-alcohol(obtained via selective reduction of the keto group as described above)with the appropriate acylating agent conveniently under mild conditions.Useful acylating agents include the corresponding acid anhydrides, suchas acetic anhydride and propionic anhydride. Alternatively, thecorresponding acyl chloride, such as benzoyl chloride, can be employed.The reaction is usually conducted at from room temperature to aboutreflux temperature, generally in the presence of pyridine as solvent.Typical acyloxy groups thus introduced in accordance herewith are thehydrocarbon carboxylic acid acyloxy groups listed and definedhereinabove.

The following examples will serve to further typify the nature of thisinvention. As these are presented solely for the purpose ofillustration, they should not be construed as a limitation on the scopeof this invention. In some instances, for convenience, the variousisomeric forms are specified, however, it will be understood that in anyof the reaction steps, both the alpha and beta isomers at Cl,2 and C-6,7are included within the scope hereof.

EXAMPLE 1 To a suspension of 1 g. of pregn-4-ene-3,20-dione in 7.5 ml.of anhydrous, peroxide-free dioxane are added 1.2 ml. of freshlydistilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. Themixture is stirred at room temperature for 15 minutes and allowed tostand at room temperature for 30 minutes. There is then added 0.8 ml. ofpyridine, followed by water until solidification occurs. This solid iscollected by filtration, washed with water and air dried to yield3-ethoxypregna-3,5(6)- diene-3,20-dione which is recrystallized fromacetonezhexane.

To a solution of 1 g. of 3-ethoxypregna-3,5 (6)-diene- 3,20-dione in 20ml. or tetrahydrofuran, cooled to C., is added 1.05 molar equivalents of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 100 mg. ofp-toluenesulfonic acid. The resulting mixture is stirred at 0 C. for 30minutes, filtered and diluted with 100 ml. of methylene chloride. Theorganic phase is separated, washed with aqueous sodium hydroxidesolution until the washings are colorless and then with water toneutrality, dried over sodium sulfate, and evaporated to dryness toyield pregna-4,6-diene-3,20-dione which may be further purified throughrecrystallization from acetonezhexane.

A mixture of l g. of pregna-4,6-diene-3,ZO-dione, 2 g. of chloranil, andml. of n-amyl alcohol are refluxed under nitrogen for 24 hours. Themixture is then cooled, washed with a cold aqueous solution of 10%sodium hydroxide until the washings are colorless, dried over sodiumsulfate and evaporated. Chromatography of the residue on neutral aluminayields pregna-l,4,6-triene-3,20- dione which is further purified throughrecrystallization from acetone :hexane.

To a gently refluxing solution of 1 g. of pregna-1,4,6-triene-3,20-dione in ml. of dimethyl diethylene glycol ether is addedwith stirring and in a dropwise fashion a 1:2 w./v. solution of sodiumchlorodifluoroacetate in dimethyl diethylene glycol ether. The additionis stopped after the introduction of further reagent fails tosubstantially change the U.V. spectrum. The mixture is then filtered andevaporated to dryness. The residue thus obtained is chromatographed onalumina and silica with successive portions of methylenechloridezhexane, methylene chloride and methylene chloride:acetone toobtain the 1a,2ot;6a,7a bis(difluoromethylene)pregn-4-ene-3,20- dione,1,8,2,8;6,B,7fi bis(difluoromethylene)pregn-4-ene-3, 20 dione,la,2a;6fi,7fi-bis(difluoromethylene)pregn-4- ene-3,20-dione, and1B,2/3;6a,7a-bis(difluoromethylene) pregn-4-ene-3,20-dione products.

EXAMPLE 2 A mixture of 1 g. of pregn-4-en-17u-ol-3,20-dione, 1 g. ofp-toluenesulfonic acid monohydrate, 50 ml. of acetic acid and 25 ml. ofacetic anhydride is allowed to stand at room temperature for 24 hours,and then poured into water and stirred. This mixture is then extractedwith methylene chloride and these extracts are dried and evaporated toyield 17a-acetoxypregn-4-ene-3, 20-di0ne which is recrystallized fromacetonezether.

To a suspension of 1 g. of 17a-acetoxypregn-4-ene-3,20- dione in 7.5 ml.of anhydrous, peroxide-free dioxane are added 1.2 ml. of freshlydistilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. Themixture is stirred at room temperature for 15 minutes and allowed tostand at room temperature for minutes. There is then added 0.8 ml. ofpyridine, followed by water until solidification occurs. This solid iscollected by filtration, washed with water and air dried to yield3-ethoxy-l7aacetoxypregna-3,5(6)-dien-20-one which is recrystallizedfrom acetonezhexane.

A mixture of 5 g. of 3-ethoxy-17u-acetoxypregna-3, 5(6)-dien-2O-one, 2g. of anhydrous sodium acetate and 100 ml. of acetone is treated with 32ml. of water. The solution is cooled to 5 C. and 1.1 molar equivalentsof N-chlorosuccinimide and 2 ml. of glacial acetic acid are added. Themixture is stirred for 30 minutes at the same temperature and thendiluted with water. After being allowed to stand at C. for 15 hours, thesolid is collected by filtration, washed with water and dried undervacuum to yield 6/3-chcloro-17a-acetoxypregn-4- ene-3,20-dione which isrecrystallized from acetone. The corresponding 6a-Cl1l0r0 compound isobtained by dissolving this compound in glacial acetic acid andintroducing a slow stream of anhydrous hydrogen chloride over a periodof four hours and a temperature of 15 C. The solid which forms uponpouring this mixture into water is collected by filtration, washed withwater and dried to yield 6u-chloro-17a-acetoxypregn-4-ene-3,20- dionewhich is recrystallized from acetonechexane.

A mixture of 1 g. of 6a-Cl1lOrO-17 m-acetoxypregn-4-ene- 3,20-dione, 2g. of chloranil, 15 ml. of ethyl acetate and 5 ml. of acetic acid isrefluxed under nitrogen for 96 hours. The mixture is then cooled andwashed with cold aqueous sodium hydroxide until the washings werecolorless. The organic solution is dried over sodium sulfate and theethyl acetate removed by evaporation. Upon chromatography of the residueon neutral alumina there is obtained6-chloro-17a-acetoxypregna-4,6-dieue- 3,20-dione which may be furtherpurified by recrystallization from acetonezhexane.

A mixture of 1 g. of 6-chloro-17a-acetoxypregna-4,6- diene-3,20-dione, 2g. of chloranil and 10 ml. of n-amyl alcohol are refluxed under nitrogenfor 24 hours. The mixture is then cooled, Washed with a cold aqueoussolution of 10% sodium hydroxide until the washings were colorless,dried over sodium sulfate and evaporated. Chromatography of the residueon neutral alumina yields6-chloro-17u-acetoxypregna-1,4,6-triene-3,20-dione which may be furtherpurified through recrystallization from acetone hexane.

To a stirred and refluxing solution of 1 g. of 6-chloro-17a-acetoxypregna-1,4,6-triene-3,20-dione in 8 ml. of dimethyldiethylene glycol ether is added in a dropwise fashion over a two-hourperiod, a solution of 30 equivalents of sodium chlorodifiuoroacetate in30 ml. of dimethyl diethylene glycol ether. At the end of the reactionperiod, which may be followed by the UV. spectra, the mixture isfiltered and evaporated in vacuo to dryness. The residue ischromatographed on silica and alumina, eluting successively withmethylene chloride:hexane, methylene chloride and methylenechloridezacetone to obtain the1a,2a;6a,7u-bis(difluoromethylene)-6B-chloro- 17ozacetoxypregn-4-ene-3,20-dione, lB,2fi;6fi,7fi-bis(difluoromethylene) 60cchloro-17oc-acetoxypregn-4-ene-3, -dione,1a,2a;6,8,7{3-bis(difluoromethylene)-6a-chloro-17a-acetoxypregn-4-ene-3,20-dione, and lfi,2[3;6a,7a-bis(difluoromethylene) 6p-chloro-17a-acetoxypregn-4-ene- 3,20-dioneproducts.

EXAMPLE 3 To a solution of 5 g. of l6a-methylpregn-4-ene-17a,21-diol-3,20-dione in 200 ml. of chloroform are added 40 ml. of 37% aqueousformaldehyde and 5 ml. of concentrated hydrochloric acid. The mixture isstirred for 48 hours at room temperature and the two layers thenseparated. The aqueous layer is extracted with chloroform and thecombined organic layer and chloroform extracts are Washed with water toneutrality, dried over sodium sulfate, and evaporated to dryness toyield 16a-methyl- 17a,20;20,21-bis-methylenedioxypregn-4-en-3-one whichis recrystallized from methanolzether.

A mixture of 1 g. of 16a methyl l7oz,20;20,2lbismethylenedioxypregn-4-en-3-one, 2 g. of chloranil, 16 ml. of ethylacetate and 5 ml. of acetic acid is refluxed under nitrogen for 96hours. The mixture is then cooled and washed with cold 10% aqueoussodium hydroxide until the washings are colorless. The organic solutionis dried over sodium sulfate and the ethyl acetate removed byevaporation. Upon chromatography of the residue on neutral alumina,there is obtained 16a-methyl-17a,20;20,21-bismethylenedioxypregna-4,6-dien-3-one which may b further even purifiedby recrystallization from acetone: hexane.

A mixture of 1 g. of16u-methyl-l7a,20;20,21-bismethylenedioxypregna-4,6-dien-3-one, 2 g. ofchloranil and 10 ml. of n-amyl alcohol are refluxed under nitrogen for24 hours. The mixture is then cooled, washed with a cold aqueoussolution of 10% sodium hydroxide until the washings are colorless, driedover sodium sulfate and evaporated. Chromatography of the residue onneutral alumina yields 16 u-methyll :,20 ;20,2l-bismethylenedioxypregna- 1,4,6-trien-3-one which may be furtherpurified through recrystallization from acetonezhexane.

One gram of16a-methyl-17a,20;20,2l-bismethylenedioxypregna-l,4,6-trien-3-one isdispersed in 8 ml. of dimethyl diethylene glycol ether with stirring.The stirring of the resulting mixture is continued while the temperaturethereof is raised to the boiling point and maintained thereafter underreflux. A solution of 30 equivalents of sodium chlorodifluoroacetatesdispersed in 30 m1. of dimethyl diethylene glycol ether is added to therefluxing mixture. This addition is conducted in a dropwise fashion overa two-hour period while maintaining stirring. At the end of this time,the reaction mixture is filtered. The filtrate is evaporated in vacuumto a dry residue. The residue is collected and chromatographed onalumina, eluting with methylene chloride to obtain the desired 1,2;6,7-bis- (difluoromethylene)l6amethyl-l7a,20;20,21-bismethylenedioxypregn-4-en-3-one products whichinclude the 10c, 20c; 60,7oc, 1,8,2fi;6oc,7oc, 111 204; 613,713, andlfi,2fi;6,6,7fl lSO- mers.

A suspension of 1 g. of 1,2; 6,7-bis(difluoromethylene)- 16a methyl1704,20; 20,2l-bismethylenedioxypregn-4- en-3-one in 10 ml. of 48%aqueous hydrofluoric acid is stirred at 0 C. for minutes. At the end ofthis time,

the reaction mixture is neutralized with 5% aqueous potassiumbicarbonate solution and extracted with ethyl acetate. These extractsare evaporated to dryness under reduced pressure and chromatographed onsilica gel with 2:1 hexane:ethyl acetate to yield loc,2oc; 6oz,7zx-biS-(lifluoromethylene) l6a-methylpregn-4-ene-170:,21-di0l-3,ZO-dione as well as the 1B,2B;6oc,7oc,1or,2oc;6/3,7B and 1B, 2/3;6B,7Bisomers which are further purified through recrystallization fromisopropanol.

To a cooled solution (0 C.) of 3.4 g. of 10L,20t60t,70tbis(difluoromethylene a methylpregn-4-ene-17a,21- diol 3,20-dione in 20ml. of 9:1 chloroformrpyridine is added in small portions, 1.4 g. ofmethanesulfonyl chloride. The mixture is allowed to stand for 14 hoursat 0 C. and then Washed with dilute hydrochloric acid, water and sodiumbicarbonate solution. The chloroform is removed by evaporation underreduced pressure and the residue is dissolved in 20 ml. of acetone andtreated at room temperature with stirring with 4 g. of sodium iodide.Sodium thiosulfate solution is added to decolorize the mixture, followedby the addition of water. The solid which forms is collected byfiltration and dried in vacuum to yield lot,2oc;6a,70tbis(difluoromethylene)-16a-methyl- 21-iodopregn 4 ene 17a ol-3,20-dione.This material in 20 ml. of acetonitrile is treated dropwise with 1.4 g.of silver fluoride in 3 ml. of water. The mixture is allowed to stand atroom temperature for 24 hours and then filtered. The filtrate isconcentrated under vacuum and the residue is dried to yield1a,2a;6a,7a-bis(difluoromethylene)-16cxmethyl-21-fluoropregn-4-ene-l7a-ol-3,20-dionewhich is recrystallized from methanolzacetone.

In accordance with the foregoing procedures, 1a,20z;6fl, 7B bis(difluoromethylene)-16u-methyl-2l-fluoropregn-4- ene 17a ol 3,20-dione,1fl,2fl;6a,7a-bis(difluoromethyL ene) 160amethyl-21-fluoropregn-4ene-17u-ol-3,20-dione, and l,B,2B;6{3,76-bis-(difluoromethylene)-l6a-methyl-21-fluoropregn-4-ene-l7a-ol-3,20-dione also are prepared when utilizingthe respective starting compound.

Similarly, the following compounds including the respective alpha andbeta isomers separably by chromatography are obtained according to theprocedure hereof: l,2;6,7-bis-(difluoromethylene) 16Bmethyl-2l-fluoropregn 4 ene 17a ol-3,20-dione;1,2;6,7-bis(difluoromethylene) 16cc chloro-2l-fluoropregn-4-ene-1704-01-3,20-dione; and1,2;6,7-bis(difluoromethylene)-l6a,2l-difluoropregn-4-ene-l7a-ol-3,20-dione.

'EXAMPLE 4 To a suspension of 1 g. of pregn-4-ene-3,20-dione in 7.5 ml.of anhydrous peroxide-free dioxane are added 1.2 ml. of freshlydistilled ethyl orthoformate and 0.8 g. of p-toluenesulfonic acid. Themixture is stirred at room temperature for minutes and allowed to standat room temperature for 30 minutes. There is then added 0.8 ml. ofpyridine, followed by water until solidification occurs. This solid iscollected by filtration, washed with water and air dried to yield3-ethoxypregna-3,5,(6)-diene-3,20-dione which is recrystallized fromacetonezhexane.

A stream of perchloryl fluoride is passed through a $0- lution of 1 g.of 3-ethoxypregna-3,5,(6)-diene-3,20-dione in ml. of dimethylformamide,cooled to 0 C. for five minutes. After being allowed to slowly attain atemperature of 20 C., the solution is poured into water and extractedwith ethyl acetate. These extracts are washed with saturated aqueoussodium bicarbonate solution and with water to neutrality, dried oversodium sulfate and evaporated to dryness. The residue is thenchromatographed on alumina to separate the oc-fltlOlO and 63- fluoroisomers. The latter, which predominates, is dissolved in 50 ml. ofglacial acetic acid and through this solution is passed a stream of dryhydrogen chloride for a period of 24 hours and at a temperature of 15 C.The mixture is poured into cold water and the solid which forms iscollected by filtration, washed with water and dried to yield6a-fluoropregn-4-ene-3,20-dione which is recrystallized fromacetonezhexane.

One gram of 6u-fluoropregn-4-ene-3,20-dione and 2 g. of chloranil in 50ml. of t-butanol are heated at reflux for eight hours. The cooledreaction mixture is filtered and the solid thus separated is washed witha large volume of ethyl acetate. The combined filtrate and washings arein turn washed with cold 10% aqueous sodium hydroxide until the washingsare colorless, dried over sodium sulfate and evaporated to dryness toyield 6-fiuoropregna-4,6-

diene-3,20-dione which may be further purified through chromatographywith alumina and recrystallization from methylene chloride:ether.

To a stirred and refluxing solution of 1 g. of6-fluoropregna-4,6-diene-3,20-dione in 8 ml. of dimethyl diethyleneglycol ether is added in a dropwise fashion over a two-hour period, asolution of equivalents of sodium chlorodifluoroacetate in 30 ml. ofdimethyl diethylene glycol ether. At the end of the reaction period,which may be followed by the U.V. spectra, the mixture is filtered andevaporated in vacuo to dryness. The residue is added to 10% methanolicpotassium hydroxide and this mixture is heated briefly at reflux andpoured into ice water. The solid which forms is collected, washed withwater, dried and chromatographed on alumina, eluting with methylenechloride, to yield 6a,7a-difluoromethylene-6B-fluoropregn-4-ene-3,ZO-dione and 66,75 difluoromethylene-6a-fluoropregn-4-ene-3,20-dione.

A mixture of l g. of6,7-difluoromethylene-G-fluoropregn-4-ene-3,20-dione, 2 g. of chloraniland 10 ml. of n-amyl alcohol are refluxed under nitrogen for 24 hours.The mixture is then cooled, washed with a cold aqueous solution of 10%sodium hydroxide until the washings were colorless, dried over sodiumsulfate and evaporated. Chromatography of the residue on neutral aluminayields 12 6,7-difiuoromethylene-6-fluoropregna 1,4 diene-3,20-dionewhich may be further purified through recrystallization fromacetonezhexane.

To a stirred and refluxing solution of 1 g. of6,7-difluoromethylene-6-fiuoropregna-1,4-diene-3,20-dione in 8 ml. ofdimethyl diethylene glycol ether is added in dropwise fashion over atwo-hour period, a solution of 30 equivalents of sodiumchlorodifluoroacetate in 30 ml. of dimethyl diethylene glycol ether. Atthe end of the reaction period, which may be followed by the U.V.spectra, the mixture is filtered and evaporated in vacuo to dryness. Theresidue is added to 10% methanolic potassium hydroxide and this mixtureis heated briefly at reflux and poured into ice Water. The solid whichforms is collected, washed with water, dried and chromatographed onalumina, eluting with methylene chloride, to yield1a,2a;6a,7a-bis(difluoromethylene) 6B fluoropregn 4 ene-3,20-dione,lB,2fl;6oc,7ct-bl$(ClifillOIOmEtllylene)-6,6-fluoropregn 4ene-3,20-dione, 1a,2ot;6/3,7B- bis(difluorornethylene)-6a-fluoropregn 4ene-3,20-dione, and 1fl,2,8;6fi,7,8bis(difluoromethylene-6a-fluoropregn.-4-ene-3,20-dione.

The l,2;6,7-bis(difluoromethylene) products thus obtained can also beprepared by introducing the A unsaturated system in the6-fluoropregn-4-ene-3,20-dione intermediate as described above andtreating this triene as described in Examples 1, 2, or 3 with sodiumchlorodifluoroacetate.

In accordance with the above methods, the following compounds, includingeach of the respective la,2a;6ot,7ot; loc,2o;6[3,7fl; 1B,2,B;6a7a; and1fi,2,B;6,B,7,B isomers thereof are prepared:

l,2;6,7-bis(difluoromethylene) l 7oc-acetoxypregn-4-ene- 3,20-dione;

1,2;6,7-bis (difluoromethylene) pregn-4-ene-17u-o1-3,20-

dione;

1,2 ;6,7-bis (difluoromethylene) 1 6a-methylpregn-4-en- 1705-01-3,20-dione;

1,2;6,7-bis(difluoromethylene) -16[3-methylpregn-4-en- 17 oc-Ol-3,20-dione;

l,2;6,7-bis difluoromethylene) -6-methylpregn-4-ene-3,20-

dione;

1,2;6,7-bis(difluoromethylene) -6-fluoropregn-4-ene-17aol-3,20-dione;

1,2 ;6,7 -bis (difluoromethylene) -6-fluoro- 17 a-acetoxypregn-4-ene-3,20-dione;

1,2;6,7-bis (difluoromethylene) -6-chloro-16a-methylpregn-4-en- 17a-ol-3,20-dione;

1,2;6,7-bis(difluoromethylene)-6-chloro-l6a-methyl-17aacetoxypregn-4-ene-3,20-dione;

1,2;6,7-bis(difluoromethylene)-l6fl-methyl-21-chloropregn-4-ene-17a-ol-3 ,20-dione;

1,2;6,7-bis(difluoromethylene)-6,16oc-dimethylpregn-4- ene-3 ,20-dione;

1,2;6,7-bis(difluoromethylene)-6,16,8-dimethy1pregn-4- en- 17a-0l-3,20-dl0116;

1,2;6,7-bis(difluoromethylene)-6-fluoro-17o-adamantoyloxypregn-4-ene-3,20-dione;

1,2;6,7-bis(difluoromethylene)-6-fiuoro-16p-methy1-17apropionyloxypregn-4-ene-3 ,20-dione;

1,2;6,7-bis(difluoromethylene)-6,21-difiuoro-16-methylene-4-ene-3,20-dione;

l,2;6,7-bis (difluoromethylene) -17oz- (n-butyryloxy) -21-fluoropregn-4-ene-3,20-dione;

1,2;6,7-bis (difluoromethylene)-17u-caproy1oxypregn-4- ene-3 ,20-dione;

l ,2;6,7-bis(difluoromethylene)-6,16/8dimethyl-21-chloropregn4-ene-3,20-dione;

1,2;6,7-bis (difluoromethylene) -6, l6fl-dimethylpregn-4- ene-3,20-dione;

1,2 ;6,7-bis difluoromethylene -6-fluoro-l 6ot-methyl-17ccacetoxypregn-4-ene-3,20-dione;

1,2;6,7-bis (difluoromethylene -2 l-chloropregn-4-ene- 3 ,ZO-dione;

1 3 1,2 ;6,7-bis (difluoromethylene -6-ch1oro- 171x-5-chloropropionyloxy) pregn-4-ene-3 ,20-dione; and 1,6 ;6,7-bisdifluoromethylene -6-fluoro-16-methy1enepregn-4-en-l7a-ol-3 ,20-dione.

The 16oc-Chl01'0 and 16a-fluoro starting materials employed for theabove may be obtained in the following manner.20,21-oxidopregna-4,16-dien-3-one is treated with hydrogen fluoride andthen acetic anhydride in the manner described by Magerlein et al., J.Med. Chem. 7,

748 (1964) to yield 16a-fluoro-2l-acetoxypregna-4,17-

(20)-dien-3-one or with hydrogen chloride and then acetic acid in themanner of Kagan et al., J. Med. Chem. 7, 751 (1964) to yield16a-chloro-21-acetoxypregna-4,17(20)- dien-3-one. Each of thesecompounds is then oxidized with osmium tetroxide and N-methylrnorpholineoxidehydrogen peroxide, as described in both of these references, toyield 16a-fluoro-21-acetoxypregn-4-ene-17a-ol- 3,20-dine and16a-chloro-21-acetoxypregn-4-ene17a-ol- 3,20-dione, which are hydrolyzedwith base to yield the free 21-hydroxy compounds which can be removed orreplaced as described above.

EXAMPLE 5 A solution of 0.5 g. of6,7-difluoromethylene-6-fluoropregna-14,-diene-3,20-dione in 5 ml. ofdimethylsulfoxide is added to a solution of one equivalent ofdimethylsulfoxonium methylide in dimethylsulfoxide, prepared in themanner of Corey et al., JACS 87, 1353 (1965). The mixture is stirredunder nitrogen and at room temperature for 20 hours and then at 50 C.for seven hours. Fifty milliliters of water are then added and theresulting mixture extracted four times with 50 ml. portions of ethylacetate. The combined extracts are washed with water and saturatedaqueous sodium chloride solution, dried over sodium sulfate andevaporated to dryness. This residue is then chromatographed on silica,eluting with 1:9 ether1methylene chloride to yield1,2a-methylene-6u,7a-difluoromethylene-65-fluoropregn- 4-ene-3,20-dione;

15,25-methylene-6,7u-difluoromethylene-65-fluoropregn- 4-ene-3,20-dione;

1a,2a-methylene-65,75-difluoromethylene-6a-fluoropregn-4-ene-3,20-dione; and

15,25-methylene-65,75-difluoromethylene-6a-fluoropregn-4-ene-3,20-dione.

EXAMPLE 6 A mixture of 0.5 g. of Got-chloro-17a acetoxypregn-4-ene-3,20-dione, ml. of dioxane and 0.35 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone is refluxed for 10 hours. Themixture is then cooled, filtered and evaporated to dryness. The residueis dissolved in acetone and this solution is then filtered through 10 g.of alumina and concentrated to yield6u-chloro-17a-acetoxypregna-1,4-diene-3, 20-dione which is furtherpurified by recrystallization from acetonezhexane.

A solution of 0.5 g. of Got-chloro-l7a-acetoxypregna-1,4-diene-3,20-dione in 5 ml. of dimethylsulfoxide is added to asolution of 1 equivalent of dimethylsulfoxonium methylide indimethylsulfoxide, prepared in the manner of Corey et al., JACS 87, 1353(1965). The mixture is stirred under nitrogen and at room temperaturefor 20 hours and then at 50 C. for seven hours. Fifty milliliters ofwater are then added and the resulting mixture extracted four times with50 ml. of ethyl acetate. The combined extracts are Washed with H 0 andsaturated aqueous sodium chloride solution, dried over sodium sulfateand evaporated to dryness. This residue is then chromatographed onsilica, eluting with etherzmethylene chloride to yield1a,2a-methylene-6a-chloro-17a-acetoxypregn-4- ene-3,20-dione and15,25-methylene-6a-chloro-l7a-acetoxypregn-4-ene-3,20-dione.

A mixture of 1 g. of1,2-methylene-6a-chloro-17aacetoxypregn-4-ene-3,20-dione, 2 g. ofchloranil, ml.

of ethyl acetate and 5 ml. of acetic acid is refluxed under nitrogen for96 hours. The mixture is then cooled and washed with cold 10% aqueoussodium hydroxide until the washings were colorless. The organic solutionis dried over sodium sulfate and the ethyl acetate removed byevaporation. Upon chromatography of the residue on neutral alumin, thereis obtained 1,2-methylene-6a-chloro-17a-acetoxypregna-4,6-diene-3,20-dione which may be purified byrecrystallization from acetonezhexane.

To a stirring and refluxing solution of 1 g. of 1,2-methylene6a-chloro-17a-acetoxypregna-4,6-diene-3,20-dione in 8 ml. of dimethyldiethyleneglycol ether is added in a dropwise fashion over a two-hourperiod, a solution of 30 equivalents of sodium chlorodifiuoroacetate in30 ml. of dimethyl diethyleneglycol ether. At the end of the reactionperiod, which may be followed by the UV. spectra, the mixture isfiltered and evaporated in vacuo to dryness. The residue is added to 10%methanolic potassium hydroxide and this mixture is heated briefly atreflux and poured into ice Water. The solid which forms-is collected,Washed with water, dried and chromatographed on alumina, eluting withmethylene chloride, to yield1aim-methylene-6a,7ot-difiuoromethylene-65-chloro-17aacetoxypregn-4-3,20-dione;

15,25-methylene-6u,7a-difluoromethylene-65-chloro-17aacetoxypregn-4-ene-3,20-dione;

1a,2a-methylene-6 5,7 5-difluoromethylene-6a-chloro-17ozacetoxypregn-4-ene-3,ZO-dione; and

15,25-methylene-65,75-difluoromethylene-6a-chloro-17aacet0xypregn-4-ene-3,20-dione.

In accordance with the foregoing procedures, the following compounds,including each of the 104,2; 611,706 lot,2.ot; 65,75; 15,25;6a,7 x; and15,25; 65,75 isomers thereof, are prepared:

l,Z-methylene-6,7-difluoromethylenepregn-4-ene-3,20-

dione; 1,Z-methylene-6,7-difluoromethylene-l7a-acetoxypregn-4-ene-3,20-dione; 1,Z-methylene-6,7-difluoromethylene- 16OL-I1l6thY1-21-fluoropregn-4-en-l7ot-ol-3,20-dione;1,2-methylene-6,7-difluoromethylene--methyl-21- fluoropregn-4-enl7a-ol-3,20-dione; 1,Z-methylene-6,7-difluoromethylene-16a-chloro-2 1-fluoropregn-4-en- 1711-01-3 ,20-dione;1,2-methylene-6,7-difluoromethylene- 1 6a,21-difluoropregn-4-en-17a-ol-3,20-dione; 1,Z-methylene-6,7-difluoromethylenepregn-4-ene-17a-ol- 3,20-dione; 1,2-methylene-6,7-difluoromethylene-16u-methylpregn-4-en-17a-o1-3,20-dione; 1,2-methylene-6,7-difluoromethylene- 165-methylpregn- 4-enl7a-ol3,20-dione;1,2-methylene-6,7-difluoromethylene-6-methylpregn-4- ene-3,20-dione;1,Z-methylene-6,7-difluoromethylene-6-fluoropregn-4-ene-17u-ol-3,20-dione;1,2-methylene-6,7-difluoromethylene-6-fiuoro-17u-acetoxypregn-4-ene-3,20-dione;1,2-methylene-6,7-difluoromethylene-G-chloro-16a-methylpregn-4-ene-17a-ol-3,20-dione;1,Z-methylene-6,7-difluoromethylene-6-chloro-16amethyl-17a-acetoxypregn-4-ene-3,20-dione; 1,2-methylene-6,7-difluoromethylene-165-methyl-2l-chloropregn-4-ene-17a-ol-3,20-dione;l,Z-methylene-6,7-difluoromethylene-6,16oz-dimethylpregn-4-ene-3,20-dione; 1,2-methylene-6,7-difluoromethylene-6,165-dimethylpregn-4-en- 17 a-ol-3,20-dione;1,2methylene-6,7-difiuoromethylene-6-fluoro-17u-adamantoyloxypregn-4-ene-3,20-dione;1,Z-methylene-6,7-difluoromethylene-6-fluoro- 1 65-methyl-17a-propionyloxypregn-4-ene-3 ,20-dione;

1 5 1,Z-methylene-6,7-difiuoromethylene-6,21-difluoro-16-methylene-4-ene-3 ,20-dione;1,2-methylene-6,7-difluormethylene-17a-(n-butyryloxy) -21-fluoropregn-4-ene-3 ,20-dione;1,2-methylene-6,7-dil'luoromethylene-17u-caproyloxypregn-4-ene-3,20-dione; 1,2-methylene-6,7-difluoromethylene-6,16fi-dimethyl-21-chloropregn-4-ene-3 ,20-dione;1,Z-methylene-6,7-difluoromethylene-6,16fi-dimethylpregn-4-ene-3,ZO-dione;1,2-methylene-6,7-difluoromethylene-6-fiuoro-16amethyll7a-acetoxypregn-4-ene-3,ZO-dione; 1,Z-methylene-6,7-difiuoromethylene-21-chloropregn-4- ene-3,ZO-dione; 1,2-methylene-6,7-difluoromethylene-6-chloro-17a-([3-chloropropionyloxypregn-4-ene-3,20-dione; and1,2-methylene-6,7-difiuoromethylene-6-fiuoro-16-methylenepregn-4-en-17a-ol-3,20-dione.

The 16-methyl and -methylene compounds are prepared as follows.

EXAMPLE 7 To a suspension of 1 g. of1,2;6,7-bis(disfluoromethylene)-pregn-4-ene-17a-ol-3,20-dione in 27 ml.of methanol and 1 ml. of water, under nitrogen, is added 1.4 g. ofsemicarbazide hydrochloride and 0.74 g. of sodium bicarbonate. Themixture is heated at reflux for three hours and then at 45 C. for 20hours. The suspension is cooled and 36 ml. of water are slowly added.The solid is collected by filtration, washed with water and dried toyield 1,2;6,7-bis(difluoromethylene)pregn 4 ene 1704-01-3, 20-bissemicarbazone which is recrystallized from pyridinezmethanol.

A solution of 1 g. of 1,2;6,7 bis(difluoromethylene)-pregn-4-ene-17aol-3,20-bis semicarbazone in 20 ml. of acetic acid and 1ml. of acetic anhydride is heated at reflux under nitrogen for one hour.The reaction mixture is then concentrated under reduced pressure to avolume of about 12 ml. and treated with 6 ml. of water and 3 ml. ofpyruvic acid. The mixture is allowed to stand at room temperature for 40hours and at 60 C. for two hours and is then diluted with water andextracted with chloroform. These extracts are washed with water, dilutepotassium bicarbonate solution and water, dried over magnesium sulfate,and evaporated to dryness under reduced pressure. The residue ischromatographed on neutral alumina with benzene to yield 1,2;6,7-bis(difiuoromethylene)-pregna-4,16-diene-3,20-dione which may berecrystallized from acetonezether.

A solution of 1 g. of 1,2;6,7-bis(difluoromethylene)-pregna-4,16-diene-3,20-dione in 30 ml. of an ethereal solution ofdiazomethane is allowed to stand at room temperature for 24 hours. Onemilliliter of acetic acid is then added to the mixture which is thenevaporated to dryness under reduced pressure. The residue is heatedgradually to 180 C. in vacuo, cooled and recrystallized fromacetonezhexane to yield 1,2;6,7-bis(difluoromethylene)-16-methylpregna-4,16-diene-3,20-dione.

To a stirred solution of g. of1,2;6,7-bis(difluoromethylene)-16-methylpregna-4,l6-diene-3,20-dione, in350 ml. of methanol, is added 20 ml. of 4 N aqueous sodium hydroxide and20 ml. of hydrogen peroxide, maintaining a temperature of approximately15 C. The solution is allowed to stand at 0 C. for 15 hours and thenpoured into ice water. The solid which forms is collected by filtration,Washed with water, and dried to yield 1,2; 6,7-bis(difluoromethylene)16oc,l7oz -oxido 16p-methylpregn-4-ene-3,20-dione which may be furtherpurified by recrystallization from acetone:hexane.

To a solution of 1 g. of 1,2;6,7-bis(difluoromethylene)- 16a,17a-oxido166 methylpregn-4-ene-3,20-dione in 10 ml. of dioxane is added 0.5 ml.of a w./v. solution of hydrogen bromide in acetic acid. After beingallowed to stand for 10 minutes at room temperature, the mixture ispoured into Water and extracted with ether.

These ethereal extracts are dried over sodium sulfate and evaporated todryness to yield 1,2;6,7-bis (difiuoromethylene)-16-methylpregn 4en-17a-ol-3,20-dione which may be further purified throughrecrystallization from acetone:hexane.

In like manner, the 1,2-methylene-6,7-difluoromethy1- ene-16-methylpregn4 en-ol-3,20-dione compounds are prepared from1,2-methylene-6,7-difiuoron1ethylpregn-4- ene-17u-ol-3,20-dione.

Also prepared in accordance with the above are1,Z-methylene-6,7-difluoromethylene-16-methylene-17aacetoxypregn-4-ene-3,ZO-dione,

1,2;6,7-bis (difluoromethylene) -16-methylene-l7u-acetoxypregn-4-ene-3,20-dione,

1,Z-methylene-6,7-diiluoromethylene-6-chloro-16-methylene-17ot-acetoxypregn-4-ene-3,20-dione,

1,2;6,7-bis(difluoromethylene)-6-chloro-16-methylenel7a-acetoxypregn4-ene-3 ,20-dione,

1,Z-methylene-6,7-difiuoromethylene-6-fiuoro-16methylene-17a-acetoxypregn-4-ene-3,ZO-dione, and

1,2 ;6,7-bis difluoromethylene -6-fiuoro- 1 6-methylene- 17a-acetoxypregn-4-ene-3 ,20-dione.

The 16,17-alkylidenedioxy derivatives are prepared in accordance withthe following procedure.

EXAMPLE 8 To ml. of acetone containing 1 g. ofpregn-4-enel6a,l7oc-di0l3,20-di0ll6 are added 30 drops of 70% perchloricacid. The mixture is allowed to stand one hour at room temperature, 30drops of pyridine are added and the solution is evaporated to drynessunder reduced pressure. Thirty milliliters of water are added to theresidue and this mixture is extracted several times with ethyl acetate.The combined extracts are washed to neutrality with water, dried oversodium sulfate and evaporated to dry mess. The residue upon triturationwith methanol yields 16a,17a-isopropylidenedioxypregn-4-ene-3,20-dionewhich is recrystallized from methanol.

The requisite unsaturation and methylene and halomethylene groups arethen introduced in accordance with the above procedures to yield, forexample, 1,2;6,7-bis(difluoromethylene)-16a,17a isopropylidenedioxypregn4- ene-3,2 0-dione;

Similarly, the following can be prepared upon use of the appropriatestarting compounds and reagents.

1,Z-methylene-6,7-difiuor0methylene-16tx,17 x-isopr0py1-idene-dioxypregn-4-ene-3 ,ZO-dione; 1,2;6,7-bis (difluoromethylene)-6-ChlO10-16oc,17aisopropylidenedioxypregn-4-ene-3 ,20-dione;1,2-rnethylene-6,7-difluoromethylene-6-chloro-16u,17u-

isopropylidenedioxypregn-4-ene-3 ,20-dione;1,2;6,7-bis(difluoromethylene)-6,21-difluoro-16oc,17a

isopropylidenedioxypregn-4-ene-3 ,ZO-dione;1,Z-methylene-6,7-difluoromethylene-6,2 l-difiuoro-16a,17a-isopropylidenedioxypregn-4-ene-3 ,20-dione;1,2;6,7-bis(difluoromethylene)-6-methyl-16a,17otisopropylidenedioxypregn-4-ene-3,ZO-dione; 1,Z-methylene-6,7-difiuoromethylene-6-methyl-16a,17a-

isopropylidenedioxypregn-4-ene-3,20-dione;1,2;6,7-bis(difluoromethylene)-6-fiuoro-16ot,17otisopropylidenedioxypregn-4-ene-3,20-dione; 1,2-methylene-6,7-difiuoromethylene-G-fluoro-16a,17a-

isopropylidenedioxypregn-4-ene-3 ,20-dione;1,2;6,7-bis(difluoromethylene)-16u,17ot-isopropylidenedioxypregn-Z1-fluoropregn-4-ene-3,ZO-dione;1,2-methylene-6,7-difluoromethylene-16a,17a-isopropylidenedioxypregn-21-fluoropregn-4-ene-3,ZO-dione; 1,2;6,7-bis (difiuoromethylene)-1 6a,17a-(2,2-buty1idenedioxy) -pregn-4-ene-3 ,20-dione;1,2-methylene-6,7-difluoromethylene-l6a,17a (2,2-buty1- idenedioxypregn-4-ene-3 ,ZO-dione; 1 ,2;6,7-bis(difluoromethylene) -16oc,l7x-(2,2-phentylidenedioxy) -pregn-4-ene-3,20-dione;

1 7 1,Z-methylene-6,7-difluoromethylene- 1 611,1 7w(2,2-pentylidenedioxy pregn-4-ene-3 ,ZO-dione;1,2;6,7-bis(difiuoromethylene)-16a,17a-(methylphenylmethylenedioxy)pregn-4-ene-3 ,20-dione; and1,2-methylene-6,7-difiuoromethylene-1611,170:-(methylphenylmethylenedioxy)pregn-4-ene-3 ,20-dione.

Alternatively, the alkylidenedioxy grouping can be introduced into acompound which already bears the desired functionality at the C-1,2;6,7positions.

EXAMPLE 9 A mixture of 1.34 g. of 1,2;6,7-bis(difluoromethylene)-pregn-4-ene-17a,21-diol-3,20-dione, 0.38 ml. of methanesulfonylchloride, and ml. of pyridine is allowed to stand at room temperaturefor 16 hours and is then poured into ice Water and extracted withmethylene chloride. The extracts are washed with 2 N hydrochloric acid,aqueous potassium bicarbonate solution, and saturated aqueous sodiumchloride solution, dried over magnesium sulfate, and evaporated todryness. This residue and 3.6 g. of sodium iodide is added to 150 ml. ofacetone, boiled for minutes and evaporated to dryness under reducedpressure. The residue is extracted with methylene chloride. Theseextracts are washed with saturated aqueous sodium chloride solution,dried over magnesium sulfate and evaporated to dryness. A suspension ofthe residue and 2.6 g. of sodium metabisulfite in 300 ml. of 80% aqueousethanol is heated at reflux for one hour and then evaporated underreduced pressure at a temperature below C. The resiand the phases arethen separated. The organic phase is washed with saturated aqueoussodium chloride solution, dried and evaporated to dryness to yield1,2;6,7bis (difluoromethylene)-pregn-4-en-17a-ol-3 ,20-dione which maybe further purified through recrystallization from acetone2hexane.

A mixture of 1 g. of 1,2;6,7-bis (difluoromethylene)-pregn-4-en-17m-ol-3,20-dione, 1 g. of p-toluenesulfonic acidmonohydrate, ml. of acetic acid, and 25 ml. of

acetic anhydride is allowed to stand at room temperature for 24 hoursand then poured into water and stirred. This mixture is then extractedwith methylene chloride and these extracts are dried and evaporated toyield l,2;6,7- bis(difiuoromethylene) 17cc acetoxypregn 4-ene-3,20-dione which is recrystallized from acetonezether.

Similarly, 1,2 methylene6,7-difluoromethylene-17aacetoxypregn-4-ene-3,20-dione is prepared.

EXAMPLE 10 l6a,17a oxido 16B-methylpregna-4,6-diene 3,20- dione issubjected to the procedure of Example 1 to yield1,2;6,7-bis(difluoromethylene) 16a,17a oxido 16 8-methylpregn-4-ene-3,20-dione.

To a solution of 1 g. of 1,2;6,7-bis(difluoromethylene) 16a,17a oxido 163 methylpregn-4-ene-3,20-dione in 10 ml. of dioxane is added 0.5 ml. ofa 50% W./v. solution of hydrogen bromide in acetic acid. After beingallowed to stand for ten minutes at room temperature, the mixture ispoured into water and extracted with ether. These ethereal extracts aredried over sodium sulfate and evaporated to dryness to yield1,2;6,7-bis(difluoromethylene)-16-methylenepregn-4-en 17a o1 3,20-dionewhich may be further purified through recrystallization fromacetonezhexane.

A mixture of 1 g. of 1,2;6,7-'bis(difluoromethylene)- 16 methylenepregn4 en-17oc-Ol-3,20-di0n, 1 g. of ptoluene-sulfonic acid monohydrate, 50ml. of acetic acid, and 25 ml. of acetic anhydride is allowed to standat room temperature for 24 hours and then poured into water and stirred.This mixture is then extracted with methylene- 16-methy1ene-17aacetoxypregn-4-ene-3,20 dione is prepared.

EXAMPLE 11 A mixture of 1 g. of 1,2;6,7-bis(difluoromethylene)- 16ozmethylpregn-4-ene 17u-ol-3,20-dione in 15 ml. of dry chloroform, whichhas been previously washed with concentrated sulfuric acid, and 15 ml.of a 0.7 N solution of hydrogen chloride in benzyl alcohol is allowed tostand for five days with occasional shaking. At the end of this period,the solvents are removed by steam distillation and the residue extractedwith ether. The ethereal extracts are Washed well with water, dried andevaporated.

A solution of 1 g. of this material in 20 ml. of ethanol, previouslydistilled over Raney nickel, is hydrogenated with 0.25 g. of a 10%palladium-on-charcoal catalyst for 24 hours. The catalyst is thenremoved by filtration through Celite diatomaceous earth and the filtrateevaporated to dryness to yield 1,2;6,7-bis (difluoromethylene)16a-methylpregn-4-ene-3,20-dione which may be further purified byrecrystallization from acetonezhexane.

In a similar fashion,

1,2-methylene-6,7-difluoromethylene-16a-methylpregn- 4-ene-3 ,20-dione;

1,2;6,7-bis (difluoromethylene) -16,8-methylpregn-4- ene-3 ,20-dione;

1,2-methylene-6,7-difluoromethylene-l6B-methylpregn-4-ene-3 ,20-dione;

1,2;6,7-bis(difluoromethylene)-6,16a-dimethylpregn- 4-ene-3 ,20-dione;

1,2-methylene-6,7-difluorornethylene-6,16ot-dimethylpregn-4-ene-3,20-dione;

1,2;6,7-bis (difluoromethylene) -6-chloro- 1 6a-methylpregn-4-ene-3,20-dione;

O1,2-methylene-6,7-difiuoromethylene-6-chloro-16amethylpregn-4-ene-3,20-dione;

1,2 ;6,7-bis (difiuoromethylene -6,2 1 -difluoropregn-4- ene-3,20-diene;

1,2-methylene6,7-difluoromethylene-6,2 l-difluoropregn- 4-ene-3,20-dione;

1,2;6,7-bis(difluoromethylene -6-fluorol G-methylenepregn-4-ene-3,20-dione;

and 1,2-methylene-6,7-difluoromethylene-6-fiuoro-l6-methyleneprcgn-4-ene-3 ,20-dione are obtained from the corresponding17a-hydroxy derivatives.

Alternatively, the 17fi-desoxy compounds can be prepared by treating thecorresponding 3-keto-A -17-hydroxyderivative as described above to givethe 17B-desoxy intermediate followed by introduction of the C1,2 andC-6,7, unsaturation and the bis(difluoromethylene) group ormethylene-difluoromethylene group addition as described above. 1

EXAMPLE 12 A solution of 200 mg. of la,2a;6oc,7u-biS(diflu0lO-methylene)-6B-chloro-17a-acetoxy-4-ene-3,20-dione in 32 ml. of anhydrousisopropanol and 25 mg. of sodium boro-- hydride is stirred at roomtemperature for 15 hours. One hundred ml. of water is added and theresulting suspension extracted several times with ether. The ether phaseis dried over sodium sulfate and evaporated to dryness under reducedpressure to yield1u,2a;6a,7a-bis(difluoromethylene)-6,8-chloro-17a-acetoxypregn-4-en-3[3-ol-20-onewhich may be further purified by recrystallization from ether.

Also prepared are the corresponding 3,8-hydroxy derivatives of the other1,2;6,7-isomers of the respective start ing compounds. In like manner,the corresponding 35- hydroxy derivatives of the other 3-keto-Acompounds (including all isomers) prepared in accordance with theforegoing examples are prepared, for example,

1,2methylene-6,7-difiuoromethylene-6-chloro-17aacetoxypregn-4-en-3fl-ol-20-one;

1,2;6,7-bis (difluoromethylene) pregn-4-en-3 5-01-20- one;

I 9 1 ,2-methylene-6,7 -difluoromethylenep re gn-4 -en-3 8- o1-20-one;1,2;6,7-bis(difluoromethylene)-16a-methylpregn-4-ene-3fi,17a-diol-20-one;1,2-methylene-6,7-difiuoromethylene-16a-methylpregn- 4-ene-3 p,l7oz-di0l-20-OI16; 1,2;6,7-bis(difluoromethylene)16a-methyl-21-fluoropregn-4-ene-3fl,17a-diol-20=one;1,Z-methylene-6,7-difluoromethylene-16x-chloro-21- fluoropregn-4-ene-313, 1 7oc-di0l-20-0I16 1,2;6,7-bis (difluoromethylene)-16B-methyl-21-fluoropregn-4-ene-3fi,17a-diol-20-one;1,2-methylene-6,7-difluoromethylene-16B-methyl-21-fiuoropregn-4-ene-3i3,17a-diol-20-one;1,2;6,7-bis(difluoromethylene)-16a-chloro-21-fiuoropregn-4-ene-3/3,17a-diol-20-one;1,2-methylene-6,7-difluoromethylene-16a-chloro-2 1- fluoropregn-4-ene-3fl, 17a-diOl-20-Ol18;1,2;6,7-bis(difiuoromethylene)-16oz,21-difluoropregn-4-ene-3fl,17a-dio120-one;1,2-methy1ene-6,7-difluoromethylene-16a,21-difluoropregn-4-ene-3fl,17a-diol-20-one; 1,2 ;6,7-bis difluoromethylene -6-fiuoropregn-4-en- 3fl-ol-20-one; 1,2-methylene-6,7-difiuoromethylene-6-fiuoropregn-4-en-3/3-ol-20-one; 1,2 ;6,7-bis (difluoromethylene) -pregn-4-ene-3,B,170cdiol-20-one; 1,2-methy1ene-6,7-difluoromethylenepregn-4-ene-3B,17a-

diol-20 -one; 1,2;6,7-bis difiuoromethylene) -16-methy1enepregn-4-ene-3B, 17u-dio120-one; 1 ,Z-methylene-6,7-difiuoromethylene-16-methylenepregn-4-ene-3B,17a-diol-2O-or1e; 1,2;6,7-bis(difluoromethylene )6-methylpregn-4-en- 3 B-ol-20-one;1,Z-methylene-6,7-difiuoromethylene-6-methylpregn- 4-en-3 ;8-ol-20-one;1,2 ;6,7-bis difiuoromethylene) -6-fluoropregn-4-ene-3fl,

17 m-diol-ZO-one;1,2-methylene-6,7-difiuoromethylene-6-fiuoropregn-4-ene- 3 8,17a-dl0l-20-OI1C; l,2;6,7-bis difiuoromethylene -6-chlorol 6a-methy1-pregn-4-ene-3 3, 17 oc-diOl-ZO-One;1,2-methylene-6,7-difiuoromethylene-6-chloro-16oc-methylpregn-4-ene-3fi,17a-dio1-20-one;1,2;6,7-bis(difluoromethylene) -16fi-methy -2l-chloropregn-4-ene-3fl, 17u-diol-20-one;1,2-methylene-6,7-difluoromethylene-165-methyl-2lchloropregn-4-ene-3fl,17a-diol-20-one;1,2;6,7-bis(difluoromethylene) -6,16;3-dimethylpregn-4- ene-3fi,17u,dio1-20-one;1,2-methylene-6,7-difiuoromethylene-6,16fl-dimethylpregn-4-ene-3B,17a-dio1-20-one;1,2;6,7-bis(difiuoromethylene)-6,21-difiuoro-16-methylenepregn-4-en-3/3-ol-20-one;1,Z-methylene-6,7-difiuoromethylene-6,2 1-ditluoro-16-methylenepregn-4-en-313-01-20-one; 1 ,2;6,7-bis (difluoromethylene)-17oc- (n-butyryloxy) -2 1- fluoropregn-4-en-3fl-ol-20-one;1,Z-methylene-6,7-difiuoromethylene-17-(n-butyryloxy)21-fiuoropregn-4en-3fi-ol-20-one; 1,2;6,7-bis(difiuoromethylene)-6-fluoro-16 x-methyl-17aacetoxypregn-4-en-3 ,3-ol-20-one;1,2-methylene-6,7-difluoromethylene-6-fiuoro-16ot-methyl-17a-acetoXypregn-4-en-3/3-ol-20-one,1,2;6,7-bis(difluoromethylene)-16oz,17a-(isopropylidenedioxypregn-4-en-3 -01-20-one; 1,2-methylene-6,7-difluoromethylene- 16a,17a-(isopropy1- idenedioxy) -pregn-4-en-3 ,8-ol-20-one;1,2;6,7-bis(difiuoromethylene) -6-fluoro-16a,17a-(isopropylidenedioxy)pregn-4-en-3 fi-ol-ZO-one; 1,Z-methylene-6,7-difiuoromethylene-6-fluoro-1 60m, 17m- (isopropylidenedioxy) pregn-4-en-3 fl-ol-ZO-one;

20 1,2;6,7-bis(difiuoromethylene)-16a,17a-(methylpheny1- methylenedioxy)pregn-4-en-3 fi-ol-ZO-one; and1,2-methylene-6,7-difiuoromethylene-16u,17a-(methylphenylmethylenedioxy)pregn-4-en-3fi-ol-20 -one.

EXAMPLE 13 A mixture of 1 g. ofla,2a;6a,7a-bis(difluoromethylene)-6B-chloro-17a-acetoxypregn-4-en-3B-ol-ZO-one,4 m1. of pyridine and 2 ml. of acetic anhydride is allowed to stand atroom temperature for 15 hours. The mixture is then poured into ice waterand the solid which forms is collected by filtration, washed with waterand dried to yield 1a,2a;6 1,7ixbis(difiuoromethylene)-3fl,17a-diacetoxy-6fl-chloropregn-4-en-20-onewhich may be further purified through recrystallization fromacetonezhexane.

A mixture of 2 g. of111,2a;6a,7a-bis(difiuoromethylene)-6,8-chloro-17a-acetoxypregn-4-en-3Bol-20-onein 8 ml. of pyridine and 4 ml. of benzoyl chloride is heated at steambath temperatures for one hour. The mixture is then poured into icewater and the solid which forms is collected by filtration, washed withwater and dried to yield 1a,2a;6a,7abis(difluoromethylene)-3B-benzoyloxy-6,8-chloro-17a-acetoxypregn-4-en-20-one which is further purifiedthrough recrystallization from methylene chloridezhexane.

A mixture of 2 g. of 1a,2a;6a,7ix-bis(difiuoromethylene)6fl-chloro-l7ot-acetoxypregn-4-en-3fi-ol-20-one in 8 ml. of pyridine and4 ml. of adamantoyl chloride is heated at steam bath temperatures forone hour. The mixture is then poured into ice water and the solid whichforms is collected by filtration, washed with water and dried to yield1a,2a;6ix,7a-bis(difluoromethylene)3/3- adamantoyloxy 68-chloro-l7a-acetoxypregn-4-en-20-one which is further purified throughrecrystallization from methylene chloride2hexane.

The other l,2;6,7-isomers corresponding to these esters are likewiseprepared from their respective starting compound. In like manner, thecorresponding esters of the other 3B-hydroxy compounds listed above areprepared, for example,1,2-methylene-3;8,17a-diacetoxy-6-chloro-6,7-difluoromethylenepregn-4-en-20-one;1,2;6,7-bis(difluoromethylene)-3B-acetoXypregn-4-en-20- one;1,2-methylene-6,7-difluoromethy1ene-3B-acetoxypregn-4- en-20-one;1,2;6,7-bis(difluoromethylene)-3,B-acetoxy-Mot-methylpregn-4-en-17a-ol-20-one;1,2-methylene-6,7-difluoromethylene-3fi-acetoxy-16amethylpregn-4-en-l7a-ol-20-one;1,2;6,7-bis(difluoromethylene)-3B-acetoxy-16a-methyl-21-fluoropregn-4-en- 17a-ol-20-one;1,Z-methylene-6,7-difluoromethylene-3B-flcetoxy-l6amethyl-2l-fiuoropregn-4-en-17u-ol-20-one;1,2;6,7-bis(difiuoromethylene)-3B-acetoxy-16,8-methyl-21-fiuoropregn-4-en-17a-ol-20-one; 1,2-methylene-6,7-difiuoromethylene-3B-acetoxy-16(3-methyl-21-fluoropregn-4-en-17a-ol-20-one; and so forth,1,2;6,7-bis(difiuoromethylene)-3fl-benzoyloxypregn-4-en- 20-one;1,2-methylene-6,7-difiuoromethylene-BB-benzoyloxypregn- 4-en-20-one;1,2;6,7-bis difiuoromethylene)-3fi-benzoyloxy-16umethylpregn-4-en-l7oc-ol-20-one;1,2-methylene-6,7-difiuoromethylene-3B-benzoyloxy-16a-methlylpregn-4-en-17-ol-20-one;1,2;6,7-bis(difluoromethylene)-3}8-benzoyloxy-16amethyl-21-fluoropregn-4-en-17u-o1-20-one;1,Z-methylene-6,7-difluoromethylene-3p-benzoyloxy-16a-methyl-21-fluoropregn-4-ene-17a-ol-20-one;1,2;6,7-bis(difluoromethylene) -3B-benzoyloxy-16/3-methyl-21-fiuoropregn-4-en-17u-ol-20-one,1,'2-methylene-6,7-difluoromethylene-Sfi-benzoyloxy-l6/3-methyl-21-fiuoropregn-4-en-17u-ol-20-one, and so forth,

Similarly, the corresponding 3B-propionates, -caproate, -undeeanoate,-enanthate and the like esters of the above compounds can be preparedupon treatment of the respective 3fl-hydroxy compound with theappropriate acid anhydride or acid chloride.

EXAMPLE 14 Two milliliters of dihydropyran are added to a solution of 1g. of la,2a;6a,7a-bis(difluoromethylene)-6,B-chloro-17ot-acetoxypregn-4-ene-3B-ol-20-dione in ml. of benzene. About 1 ml. isremoved by distillation to remove moisture and 0.4 g. ofp-toluenesulfonyl chloride is added to the cooled solution. This mixtureis allowed to stand at room temperature for four days, and is thenwashed with aqueous sodium carbonate solution and water, dried andevaporated. The residue is chromatographed on neutral alumina, elutingwith hexane, to yield 1a,2zx;6oc7abis(difluoromethylene)- 3 3-tetrahydropyran-Z-yloxy-6B- chloro-l7a-acetoxypregn-4-en-20-one whichis recrystallized from pentane.

To a solution of l g. ofl(1,204;6a,7a-bis(difiuoromethylene)-6/3-chloro-17a-acetoxypregn-4-ene-3;8-ol-20-dionein ml. of benzene, is added 20 ml. of dihydrofuran. Five milliliters isdistilled off to remove moisture, and the mixture is allowed to cool toroom temperature. To the cooled mixture, 0.2 g. of freshly purifiedp-toluenesulfonyl chloride is added. The mixture is stirred at roomtemperature for 24 hours and then poured into an excess of 5% aqueoussodium bicarbonate solution. The product is extracted with ethylacetate, the organic solution is washed with water to neutral, driedover anhydrous magnesium sulfate, and evaporated to dryness underreduced pressure. The oily residue crystallizes on the addition of etherto yield the 1a,2a;6u,7a-bis(difluoromethylene)-3B-tetrahydrofuran- 2-yloxy-6,8-chloro-17u-acetoxypregn-4'en-20- one.

The 35-ethers of the other 1,2;6,7-isomers are likewise prepared. Inlike manner, the corresponding ethers of the other 3,3-hydroxy compoundslisted above are prepared, for example,

1,2-methylene-3,B-tetrahydropyran-Z-yloxy-6-chloro-6,7-

difluoromethylene-17u-acetoxypregn-4-en-20-one 1,2-methylene-3B-tetrahydrofuran-2-yloxy-6-chloro-6,7- difiuoromethylenel7a-acetoxypregn-4-en-20-one;

1,2;6,7-bis difluoromethylene) -3B-tetrahydropyran-2-yloxypregn-4-en-20-one;

1,Z-methylene-6,7-difiuoromethylene-3fi-tetrahydropyran-2-yloxypregn-4-en-20-one;

1,2 ;6,7-bis (difluoromethylene -3/3-tetrahydrofuran-2- Yyloxypregn-4-en-20-one;

1,Z-methylene-6,7-difiuoromethylene-3 B-tetrahydrofuran-2-yloxypregn-4-en-20- one 1,2;6,7-bis (difluo romethylene) -3;8-tetrahydropyran-2- yloxy-l 6a-methylpregn-4-enl7a-ol-20-one;

1,2-methylene-6,7-difluoromethylene-Sfi-ttrahydropyran- 2-yloxy-16u-methylpregn-4-en-17u-o1-20-one;

1,2;6,7-bis(difluoromethylene)-3 8-tetrahydrofuran-2-yloxy-l6a-methylpregn-4-en-l7u-ol-20-one;

1,2-methylene-6,7-difluorornethylene-3 ,B-tetrahydrofuran-2-yloxy-16u-methylpregn-4-en-17u-ol-20-one;

,. and so forth. 0

What is claimed is: 1. The compound of one of the formulas:

CH3 CH3 CH2R1 (|3II2R1 I 0:0 0:0 0H. 1 e111 wherein:

R is hydrogen, hydroxy or a hydrocarbon carboxylic acyloxy group of lessthan 12 carbon atoms;

R is hydrogen, methylene, a-methyl, fi-methyl or,

when taken together with R the group.

in which A is hydrogen or alkyl of up to eight carbon atoms and B ishydrogen or alkyl or aryl of up to eight carbon atoms;

R is hydrogen, methyl, chloro or fluoro; and

R is the group in which R is hydrogen, tetrahydrofuran-Z-yl,tetrahydropyran-Z-yl or a hydrocarbon carboxylic acyl group of less than12 carbon atoms.

2. The compound claimed in claim 1 wherein R is hydrogen, chloro orfluoro.

3. The compound of Formula A of claim 1 wherein R is acetoxy, R ismethylene and R is hydrogen.

4. The compound of Formula A of claim 1 wherein R is acetoxy, R ismethylene and R is chloro.

5. The compound of Formula Aof claim 1 wherein R is acetoxy, R ismethylene and R is fluoro.

6. The compound of Formula A of claim 1 wherein R is acetoxy, R ishydrogen and R is hydrogen.

7. The compound of Formula A of claim 1 wherein R is acetoxy, R ishydrogen and R is chloro.

8. The compound of Formula A of claim 1 wherein R is acetoxy, R ishydrogen and R is fluoro.

9. The compound of one of the formulas:

l-.... 2r CH2 1 CH2 i wherein:

R is fluoro or chloro;

23 R is hydrogen, hydroxy or a hydrocarbon carboxylic acyloxy group ofless than 12 carbon atoms; R is hydrogen, methylene, a-methyl, fi-methylor,

when taken together with R the group in which A is hydrogen or alkyl ofup to eight carbon atoms and B is hydrogen or alkyl of up to eightcarbon atoms;

R is hydrogen, methyl, chloro or fluoro; and

R is the group in which R is hydrogen, tetrahydrofuran-Z-yl,tetrahydropyran-Z-yl or a hydrocarbon carboxylic acyl group of less than12 carbon atoms. 10. The compound claimed in claim 9 wherein R ishydrogen, chloro or fluoro.

11. The compound of Formula C of claim 9 wherein R is acetoxy, R ismethylene and R is hydrogen.

12. The compound of Formula C of claim 9 wherein R is acetoxy, R ismethylene and R is chloro.

13. The compound of Formula C of claim 9 wherein R is acetoxy, R ismethylene and R is fluoro.

14. The compound of Formula C of claim 9 wherein R is acetoxy, R ishydrogen and R is hydrogen.

15. The compound of Formula C of claim 9 wherein R is acetoxy, R ishydrogen and R is chloro.

16. The compound of Formula C of claim 9 wherein R is acetoxy, R ishydrogen and R is fluoro.

17. The compound of one of the formulas:

R is hydrogen, hydroxy or a hydrocarbon carboxylic acyloxy group of lessthan 12 carbon atoms; and

R is hydrogen, methyl, chloro or fluoro.

18. The compound of Formula G of claim 17 wherein R is acetoxy and R ishydrogen.

19. The compound of Formula G of claim 17 wherein R is acetoxy and R ischloro.

20. The compound of Formula G of claim 17 wherein R is acetoxy and R isfluoro.

21. The compound of Formula H of claim 17 wherein R is acetoxy and R ishydrogen.

22. The compound of Formula H of claim 17 wherein R is acetoxy and R ischloro.

23. The compound of Formula H of claim 17 wherein R is acetoxy and R isfluoro.

24 24. The compound of one of the formulas:

CH3 CH3 CH3 CH3 R CF;

wherein:

R is hydrogen, hydroxy or a hydrocarbon carhoxylic acyloxy group of lessthan 12 carbon atoms; R is hydrogen, methyl, chloro or fluoro; and

R is the group RO in which R is hydrogen, tetrahydrofuran-Z-yl,tetrahydropyran-Z-yl or hydrocarbon carboxylic acyl group of less than12 carbon atoms. 25. The compound of Formula A of claim 24 wherein R isacetoxy, and R is hydrogen.

26. The compound of Formula A of claim 24 wherein R is acetoxy and R ischloro.

27. The compound of Formula A of claim 24 wherein R is acetoxy and R isfluoro.

28. The compound of one of the formulas:

R is hydrogen, methyl, chloro or fluoro; and R is the group H RO-E inwhich R is hydrogen, tetrahydrofuran-Z-yl, tetrahydropyran-Z-yl or ahydrocarbon carboxylic acyl group of less than 12 carbon atoms. 29. Thecompound of Formula C of claim 28 wherein R is acetoxy and R ishydrogen.

30. The compound of Formula C of claim 28 wherein R is acetoxy and R ischloro.

31. The compound of Formula C of claim 28 wherein R is acetoxy and R isfluoro.

References Cited UNITED STATES PATENTS 3,047,566 7/ 1962 Godtfredsen eta1. 3,200,113 8/1965 Christiansen et a1. 3,243,434 3/ 1966 Krakower.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,557,160 Dated January 19, 1971 Inventor(s) Colin C. Beard, AlexanderD. Cross It is certified that error appears in the above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 63, "ecah" should be each Column 4, line 7, delete thesecond occurence of "which" Column 4, line 64, "dichlroacetic" should bedichloroacetic Column 4, line 75, "carobn" should be carbon Column 5,line 55, "3-keto-A diene" should be 3keto-L\ diene Column 5, line 66,"staring" should be starting Column 6, line 16, "grouping" should begroupings Column 6, line 59, "chlorinal" should be chloranil Column 7,line 3, "2-iodo" should be 2liodo Column 7, line 38, "3ketosubstituted"should be 3-keto-6-substituted- Column 10, line 7, after "further" andbefore "purified" delete "even".

Column 13, line 26, "pregna-l4,diene" should be pregna-l,4-diene Column14, line 7, "alumin, should be alumina,

Column 14, line 25, "acetoxypregn43, 20-dione; should beacetoxypregn-4-ene-3,20-dione;

Column 16, line 3, "ene) l6methylpregn" should be ene)l6-methylenepregn- Column 16, line 7,"ene-l6-methylpregn-4-en-ol-3,20-dione" should beene-l6-methylenepregn-4-en-l7oLol-3, 20-dione Column 16, line 8, l,2-methylene-6,7-difluoromethylpregnshould be l, 2-methylene-6,7-difluoromethylenepregn- Column 16, line 74, "l, 2 7 6,7-bis(difluoromethylene) l6on, l7 (2, 2phentyl-" should be l, 2; 6,7-bis(difluoromethylene) 16d, l7d(2,2pentyl Column 17, lines 30 to 31, after"The resi" (line 30) and before "and the phases" (line 31) insert due ispartitio between water and methylene chloride UNITED STATES PATENTOFFICE CERTIFICATE OF CORRECTION Patent No. 3 557 160 Dated January 191971 Inventor(s) Paqe -2- It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below:

Column 18 line 38, "diene; should be dione; Column 19, line 9,l6OLchloro2l" should be l6d-meth 21- Column 20 line 67,lGCJL-methlylpregnl-sn-l7ol-20one; should bel60Lmethylpregn4en17d-ol-20-one;

Column 24, Claim 24, formula (B should appear as follow Signed andsealed this hth day of July 1972.

(SEAL) Attest:

EDIIJAW WFIETCHE'R,JRQ ROBERT GUT'PRCH-ILK Attesting OfficerCommissioner of Patents FORM PO-IOSD HO-69)

